HIV-1 is considered to be the causative agent of Acquired Immunodeficiency Syndrome (AIDS) in the United States. HIV-1 infection is characterized by an asymptomatic period between infection with the virus and the development of AIDS. The rate of progression to AIDS varies among infected individuals. AIDS involves the infection and eventual depletion of a particular type of cell of the immune system, cells that have a protein named CD4 protein on their surface (CD4-positive cells). Helper T cells and monocytes/macrophages are CD4-positive cells.
The process by which HIV-1 infects human cells involves interaction of proteins on the surface of the virus with proteins on the surface of the cells. The common understanding is that the first step in HIV infection is the binding of HIV-1 glycoprotein (gp) 120 to cellular CD4 protein. The viral gp120 then changes conformation or shape and binds to yet other cell surface proteins, such as CCR5 or CXCR4 proteins, allowing subsequent fusion of the virus with the cell. CD4 has thus been described as the primary receptor for HIV-1 and the other cell surface proteins as coreceptors for HIV-1.
More recently, there have been reports of certain HIV-1 viruses that can infect cells without binding to CD4. In Dumonceaux et al., J. Virol., 72(1): 512-519 (1998), the authors describe an HIV-1 strain that is capable of infecting cells that do not have CD4 on their surface. They observe that the amino acid sequence of the gp120 of that HIV-1 strain had changed in a way that altered the gp120 conformation and enabled it to bind to the coreceptor CXCR4 without first binding to CD4. The HIV-1 strain described in the article is a long-term laboratory culture rather than a primary isolate (a virus sample obtained directly from an infected individual). In Kolchinsky et al., J. Virol., 73(10): 8120-8126 (1999), the authors report adapting a HIV-1 virus to infect canine cells lacking CD4 on their surface. The adapted virus was able to bind CCR5 without first binding CD4. They also attribute this CD4-independent infection to changes in the amino acid sequence and conformation of the gp120 of their virus.
While the foregoing reports involved HIV-1 sequence changes in the laboratory, HIV-1 is known to undergo sequence changes in infected individuals. Termed viral evolution, viral sequence changes are believed to be one of the mechanisms by which HIV-1 evades the human immune response. For example, HIV-1 sequence changes that allow it to utilize different coreceptors and thereby infect different types of cells have been described in Shankarappa et al., J. Virol., 73(12): 10489-10502 (1999) and Hoffman et al., Proc. Nati. Acad. Sci. USA, 95:11360-11365 (1998).
Another type of immune system cell, cytotoxic T lymphocytes that express the CD8 protein on their surface (CD8-positive cells), play an important protective role against HIV-1. CD8-positive T cells kill HIV-infected cells and release antiviral factors which are thought to inhibit the replication of HIV-1 and prevent progression to AIDS. Previous studies have demonstrated that HIV-1 can occasionally infect CD8-positive T cells, but infection of the CD8-positive cells was attributed to binding of the virus to CD4 receptors on the cells. See, Flamand et al., Proc. Natl. Acad. Sci. USA, 95: 3111-3116 (1998) and Kitchen et al., J. Virol., 72: 9054-9060 (1998). The authors of Kaneko et al., J. Virol., 7(11): 8918-8922 (1997) had previously reported that HIV-2 gp105, but not HIV-1 gp120, can bind to the CD8 protein on human cells. HIV-2 is another human immunodeficiency virus that causes AIDS and is prevalent in developing countries. It is more closely related to simian immunodeficiency virus (SIV) than to HIV-1 but also uses CD4 as its primary receptor for infection. Declines in both the number of CD8-positive T cells and specific anti-HIV cytotoxic activity are associated with the onset of AIDS.
There thus remains a need in art for a more complete understanding of the type of human cells infected by HIV-1 as well as the mechanism by which infection occurs to allow the development of vaccines to prevent, and drugs to treat, HIV-1 infection.